Alzheimer's Disease (AD) is a degenerative disorder of the human central nervous system characterized by progressive memory impairment and cognitive and intellectual decline during mid to late adult life (Katzman (1986) N. Eng. J. Med. 314:964-973). The disease is accompanied by a constellation of neuropathologic features principal amongst which are the presence of extracellular amyloid or senile plaques and the neurofibrillary degeneration of neurons. The etiology of this disease is complex, although in some families it appears to be inherited as an autosomal dominant trait. However, even amongst these inherited forms of AD, there are at least three different genes which confer inherited susceptibility to this disease (St. George-Hyslop et al. (1990) Nature 347:194-197). The .epsilon.4 (C112R) allelic polymorphism of the Apolipoprotein E (ApoE) gene has been associated with AD in a significant proportion of cases with onset late in life (Saunders et al. (1993) Neurology 43:1467-1472; Strittmatter et al. (1993) Proc. Natl. Acad. Sci. (USA) 90:1977-1981). Similarly, a very small proportion of familial cases with onset before age 65 years have been associated with mutations in the .beta.-amyloid precursor protein (APP) gene (Chartier-Harlin et al. (1991) Nature 353:844-846; Goate et al. (1991) Nature 349:704-706; Murrell et al. (1991) Science 254:97-99; Karlinsky et al. (1992) Neurology 42:1445-1453; Mullan et al. (1992) Nature Genetics 1:345-347). A third locus (AD3) associated with a larger proportion of cases with early onset AD has recently been mapped to chromosome 14q24.3 (Schellenberg et al. (1992) Science 258:668-670; St. George-Hyslop et al., (1992) Nature Genetics 2:330-334; Van Broeckhoven et al. (1992) Nature Genetics 2:335-339).
Although the chromosome 14q region carries several genes which could be regarded as candidate genes for the site of mutations associated with AD3 (e.g., cFOS, alpha-1-antichymotrypsin, and cathepsin G), most of these candidate genes have been excluded on the basis of their physical location outside the AD3 region and/or the absence of mutations in their respective open reading frames (Schellenberg et al. (1992) Science 258:668-670; Van Broeckhoven et al. (1992) Nature Genetics 2:335-339; Rogaev et al. (1993) Neurology 43:2275-2279; Wong et al. (1993) Neurosci. Lett. 152:96-98).
There have been several developments and commercial directions or strategies in respect of treatment of Alzheimer's Disease and diagnosis thereof Published PCT application WO/94 23049 describes transfection of high molecular weight YAC DNA into specific mouse cells. This method may be used to analyze large gene complexes. For example, the transgenic mice may have increased APP gene dosage, which mimics the trisomic condition that prevails in Down's Syndrome, and allows the generation of animal models with .beta.-amyloidosis similar to that prevalent in individuals with Alzheimer's Disease. Published International Patent Application No. WO 94/00569 describes transgenic non-human animals harboring large transgenes such as the transgene comprising a human APP gene. Such animal models can provide useful models of human genetic diseases such as Alzheimer's Disease.
Canadian Patent Application No. 2,096,911 describes a nucleic acid coding for an APP-cleaving protease, which is associated with Alzheimer's Disease and Down's syndrome. The genetic information, which was isolated from chromosome 19, may be used to diagnose Alzheimer's Disease. Canadian Patent Application No. 2,071,105, describes detection and treatment of inherited or acquired Alzheimer's Disease by the use of YAC nucleotide sequences. The YACs are identified by the numbers 23CB10, 28CA12 and 26FF3.
U.S. Pat. No. 5,297,562, describes detection of Alzheimer's Disease associated with trisomy of chromosome 21. Treatment involves methods for reducing the proliferation of chromosome 21 trisomy. Canadian Patent application No. 2054302 describes monoclonal antibodies which recognize a human brain cell nucleus protein encoded by chromosome 21 and are used to detect changes of expression due to Alzheimer's Disease or Down's Syndrome. The monoclonal antibody is specific to a protein encoded by human chromosome 21 and is found in large pyramidal cells of human brain tissue.